Evaluation of in vitro and in vivo activity of a multityrosine kinase inhibitor, AL3810, against human thyroid cancer

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.

Download Full-text

Thyroid Cancer Detection by Ultrasound Molecular Imaging with SHP2-Targeted Perfluorocarbon Nanoparticles

Contrast Media & Molecular Imaging ◽

10.1155/2018/8710862 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

ZhongQian Hu ◽

Bin Yang ◽

Tiankuan Li ◽

Jia Li

Keyword(s):

Thyroid Cancer ◽

Molecular Imaging ◽

Diagnostic Accuracy ◽

Protein Tyrosine Phosphatases ◽

Ultrasound Contrast Agents ◽

Human Thyroid ◽

Thyroid Tumour ◽

Ultrasound Molecular Imaging

Background. Contrast-enhanced ultrasound imaging has been widely used in the ultrasound diagnosis of a variety of tumours with high diagnostic accuracy, especially in patients with hepatic carcinoma, while its application is rarely reported in thyroid cancer. The currently used ultrasound contrast agents, microbubbles, cannot be targeted to molecular markers expressed in tumour cells due to their big size, leading to a big challenge for ultrasound molecular imaging. Phase-changeable perfluorocarbon nanoparticles may resolve the penetrability limitation of microbubbles and serve as a promising probe for ultrasound molecular imaging. Methods. 65 thyroid tumour samples and 40 normal samples adjacent to thyroid cancers were determined for SHP2 expression by IHC. SHP2-targeted PLGA nanoparticles (NPs-SHP2) encapsulating perfluoropentane (PFP) were prepared with PLGA-PEG as a shell material, and their specific target-binding ability was assessed in vitro and in vivo, and the effect on the enhancement of ultrasonic imaging induced by LIFU was studied in vivo. Results. In the present study, we verified that tumour overexpression of SHP2 and other protein tyrosine phosphatases regulated several cellular processes and contributed to tumorigenesis, which could be introduced to ultrasound molecular imaging for differentiating normal from malignant thyroid diagnostic nodes. The IHC test showed remarkably high expression of SHP2 in human thyroid carcinoma specimens. In thyroid tumour xenografts in mice, the imaging signal was significantly enhanced by SHP2-targeted nanoparticles after LIFU induction. Conclusion. This study provides a basis for preclinical exploration of ultrasound molecular imaging with NPs-SHP2 for clinical thyroid nodule detection to enhance diagnostic accuracy.

Download Full-text

Antitumor effects of anlotinib in thyroid cancer

Endocrine Related Cancer ◽

10.1530/erc-17-0558 ◽

2019 ◽

Vol 26 (1) ◽

pp. 153-164 ◽

Cited By ~ 11

Author(s):

Xianhui Ruan ◽

Xianle Shi ◽

Qiman Dong ◽

Yang Yu ◽

Xiukun Hou ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Kinase Inhibitor ◽

Anaplastic Thyroid Cancer ◽

Cancer Type ◽

Papillary Thyroid ◽

Antitumor Effects ◽

Effective Therapeutic Strategy

There is no effective treatment for patients with poorly differentiated papillary thyroid cancer or anaplastic thyroid cancer (ATC). Anlotinib, a multi-kinase inhibitor, has already shown antitumor effects in various types of carcinoma in a phase I clinical trial. In this study, we aimed to better understand the effect and efficacy of anlotinib against thyroid carcinoma cells in vitro and in vivo. We found that anlotinib inhibits the cell viability of papillary thyroid cancer and ATC cell lines, likely due to abnormal spindle assembly, G2/M arrest, and activation of TP53 upon anlotinib treatment. Moreover, anlotinib suppresses the migration of thyroid cancer cells in vitro and the growth of xenograft thyroid tumors in mice. Our data demonstrate that anlotinib has significant anticancer activity in thyroid cancer, and potentially offers an effective therapeutic strategy for patients of advanced thyroid cancer type.

Download Full-text

BRAF activates and physically interacts with PAK to regulate cell motility

Endocrine Related Cancer ◽

10.1530/erc-14-0424 ◽

2014 ◽

Vol 21 (6) ◽

pp. 865-877 ◽

Cited By ~ 7

Author(s):

Samantha K McCarty ◽

Motoyasu Saji ◽

Xiaoli Zhang ◽

Christina M Knippler ◽

Lawrence S Kirschner ◽

...

Keyword(s):

Thyroid Cancer ◽

Cell Motility ◽

Cell Lines ◽

Cancer Cell ◽

Human Thyroid ◽

Thyroid Cancer Cell ◽

Cancer Cell Motility ◽

Thyroid Cancer Cell Lines

Increased p21-activated kinase (PAK) signaling and expression have been identified in the invasive fronts of aggressive papillary thyroid cancers (PTCs), including those withRET/PTC, BRAFV600E, and mutantRASexpression. Functionally, thyroid cancer cell motilityin vitrois dependent on group 1 PAKs, particularly PAK1. In this study, we hypothesize that BRAF, a central kinase in PTC tumorigenesis and invasion, regulates thyroid cancer cell motility in part through PAK activation. Using three well-characterized human thyroid cancer cell lines, we demonstrated in all cell lines thatBRAFknockdown reduced PAK phosphorylation of direct downstream targets. In contrast, inhibition of MEK activity either pharmacologically or with siRNA did not reduce PAK activity, indicating MEK is dispensable for PAK activity. Inhibition of cell migration through BRAF loss is rescued by overexpression of either constitutive active MEK1 or PAK1, demonstrating that both signaling pathways are involved in BRAF-regulated cell motility. To further characterize BRAF–PAK signaling, immunofluorescence and immunoprecipitation demonstrated that both exogenously overexpressed and endogenous PAK1 and BRAF co-localize and physically interact, and that this interaction was enhanced in mitosis. Finally, we demonstrated that acute induction of BRAFV600E expressionin vivoin murine thyroid glands results in increased PAK expression and activity confirming a positive signaling relationshipin vivo. In conclusion, we have identified a signaling pathway in thyroid cancer cells which BRAF activates and physically interacts with PAK and regulates cell motility.

Download Full-text

Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer

Endocrine Related Cancer ◽

10.1677/erc-06-0030 ◽

2007 ◽

Vol 14 (2) ◽

pp. 405-420 ◽

Cited By ~ 23

Author(s):

Gennaro Chiappetta ◽

Carmela De Marco ◽

Alfina Quintiero ◽

Daniela Califano ◽

Simona Gherardi ◽

...

Keyword(s):

Thyroid Cancer ◽

Cell Lines ◽

Kinase Inhibitor ◽

Human Cancer ◽

Inverse Correlation ◽

S Phase ◽

Human Thyroid ◽

Skp2 Expression ◽

Skp2 Protein

Loss of expression of the cyclin-dependent kinase inhibitor p27 through enhanced protein degradation frequently occurs in human cancer. Degradation of p27 requires ubiquitination by the S-phase kinase-associated protein 2 (Skp2), a member of the F-box family of Skp1–Cullin–F-box protein ubiquitin ligases. In the present study, we have investigated the role of Skp2 in human thyroid tumours. Immunohistochemistry analysis showed that Skp2 was overexpressed significantly in thyroid carcinomas (26 out of 51) compared with goitres (0 out of 12, P<0.001) or adenomas (1 out of 10, P<0.05), and that high Skp2 expression was detected more often in anaplastic thyroid (ATC; 83%, n=12) than follicular thyroid (FTC; 40%, n=20) or papillary thyroid (PTC; 42%, n=19) carcinomas (P<0.05). Thyroid cancer cell lines and tissues with high levels of Skp2 protein presented high p27 degradation activity and there was an inverse correlation between Skp2 and p27 expression in thyroid cancer tissues (n=68; P<0.05). In most cases, the observed overexpression of Skp2 protein was paralleled by an increase in the levels of Skp2 mRNA, and we observed Skp2 gene amplification at 5p13 in 2 out of 6 cell lines and in 9 out of 23 primary tumours (six out of eight ATCs, two out of nine PTCs and one out of six FTCs) using Q-PCR and/or fluorescence in situ hybridization analysis. Finally, in vitro experiments demonstrated that suppression of Skp2 expression drastically reduced proliferation of thyroid cancer cells and, conversely, forced expression of Skp2 circumvented serum dependency and contact inhibition in Skp2-negative cells by promoting p27 degradation. These findings indicate that Skp2 plays an important role for the development of thyroid cancer.

Download Full-text

Sunitinib in the Treatment of Thyroid Cancer

Current Medicinal Chemistry ◽

10.2174/0929867324666171006165942 ◽

2019 ◽

Vol 26 (6) ◽

pp. 963-972 ◽

Cited By ~ 12

Author(s):

Silvia Martina Ferrari ◽

Marco Centanni ◽

Camilla Virili ◽

Mario Miccoli ◽

Paola Ferrari ◽

...

Keyword(s):

Thyroid Cancer ◽

Growth Factor ◽

Tyrosine Kinase ◽

Kinase Inhibitor ◽

Growth Factor Receptors ◽

Phase Iii ◽

Sodium Iodide Symporter ◽

Cell Counts

Background: Sunitinib (SU11248) is an oral multi-target tyrosine kinase inhibitor (TKI) with low molecular weight, that inhibits platelet-derived growth factor receptors (PDGF-Rs) and vascular endothelial growth factor receptors (VEGFRs), c-KIT, fms-related tyrosine kinase 3 (FLT3) and RET. The concurrent inhibition of these pathways reduces tumor vascularization and causes cancer cell apoptosis, inducing a tumor shrinkage. Sunitinib is approved for the treatment of imatinib-resistant gastrointestinal stromal tumor (GIST), renal carcinoma, and pancreatic neuroendocrine tumors. Methods: We searched the literature on PubMed library. Results: In vitro studies showed that sunitinib targeted the cytosolic MEK/ERK and SAPK/JNK pathways in the RET/PTC1 cell inhibiting cell proliferation and causing stimulation of sodium/iodide symporter (NIS) gene expression in RET/PTC1 cells. Furthermore sunitinib is active in vitro and in vivo against anaplastic thyroid cancer (ATC) cells. Most of the clinical studies report that sunitinib is effective as first- and second-line TKI therapy in patients with advanced dedifferentiated thyroid cancer (DeTC), or medullary thyroid cancer (MTC). Sunitinib 37.5 mg/day is well tolerated, and effective. The most common adverse events include: reduction in blood cell counts (in particular leukocytes), hand-foot skin reaction, diarrhea, fatigue, nausea, hypertension, and musculoskeletal pain. Conclusion: Even if sunitinib is promising in the therapy of differentiated thyroid carcinoma (DTC), until now no phase III studies have been published, and additional prospective researches are necessary in order to evaluate the real efficacy of sunitinib in aggressive thyroid cancer.

Download Full-text

Expression of Leptin Receptor and Effects of Leptin on Papillary Thyroid Carcinoma Cells

International Journal of Endocrinology ◽

10.1155/2019/5031696 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Marilena Celano ◽

Valentina Maggisano ◽

Saverio Massimo Lepore ◽

Marialuisa Sponziello ◽

Valeria Pecce ◽

...

Keyword(s):

Thyroid Cancer ◽

Cell Lines ◽

Molecular Mechanisms ◽

Leptin Receptor ◽

Kinase Inhibitor ◽

Immunoblot Analysis ◽

Prolonged Treatment ◽

Papillary Thyroid

Background. Obesity has been hypothesized to contribute to the aggressiveness of thyroid cancer through the production of abnormal levels of serum adipokines. Leptin receptor (OB-R) expression has also been documented in papillary thyroid cancer (PTC). Aim. In this translational study, we analyzed in vitro the effects of leptin on the growth and migration of thyroid cancer cells (TPC-1 and K1), the molecular mechanisms underlying leptin’s action, and the influence of prolonged leptin exposure on cell response to a protein kinase inhibitor lenvatinib. The expression levels of OB-R mRNA and protein were also investigated in vivo in a series of aggressive PTCs divided into two groups based on the presence of the BRAF mutation. Results. In TPC-1 and K1 cells, prolonged treatment with leptin (500 ng/ml for 96 h) resulted in a mild increase in the proliferation (about 20% over control only in K1 cells, p<0.05) and in the migration of both cancer cell lines. Immunoblot analysis revealed a slight increase in the phosphorylation of AKT, but no effect on β-catenin and phospho-ERK expressions. The inhibitory effects of lenvatinib on the viability of both cell lines were not influenced by the leptin treatment. OB-R transcript (in fresh tissues) and proteins (in formalin-fixed and paraffin-embedded specimens) were expressed in all PTC tissues examined, with no significant differences between BRAF-mutated and BRAF-wild-type tumors. Conclusions. These results demonstrate leptin’s role in mildly increasing the aggressive phenotype of PTC cells but without influencing the action of lenvatinib. Further studies will clarify whether it is possible to target OB-R, expressed in all aggressive PTCs, as an adjuvant treatment approach for these malignancies.

Download Full-text

Honokiol, a potential therapeutic agent, induces cell cycle arrest and program cell death in vitro and in vivo in human thyroid cancer cells

Pharmacological Research ◽

10.1016/j.phrs.2016.11.038 ◽

2017 ◽

Vol 115 ◽

pp. 288-298 ◽

Cited By ~ 28

Author(s):

Chieh-Hsiang Lu ◽

Shu-Hsin Chen ◽

Yi-Sheng Chang ◽

Yi-Wen Liu ◽

Jin-Yi Wu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Thyroid Cancer ◽

Therapeutic Agent ◽

Human Thyroid ◽

Cycle Arrest ◽

Thyroid Cancer Cells ◽

Program Cell Death

Download Full-text

Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells

Cancers ◽

10.3390/cancers13174266 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4266

Author(s):

Fang-Ping Kung ◽

Yun-Ping Lim ◽

Wen-Ying Chao ◽

Yi-Sheng Zhang ◽

Hui-I Yu ◽

...

Keyword(s):

Cell Cycle ◽

Thyroid Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Human Thyroid ◽

Akt Pathway ◽

Dependent Manner ◽

Apoptosis Pathway

Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper; it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL.

Download Full-text

Evodiamine inhibits human thyroid cancer cells in vitro and in vivo

Endocrine Abstracts ◽

10.1530/endoabs.37.ep902 ◽

2015 ◽

Cited By ~ 1

Author(s):

Ying-Ray Lee ◽

Chieh-Hsiang Lu ◽

Yi-Sheng Chang ◽

Shu-Hsin Chen ◽

Yi-Wen Liu

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Human Thyroid ◽

Thyroid Cancer Cells

Download Full-text